Interleukin 12 (IL-12) is a heterodimeric polypeptide interleukin consisting of two subunits, p35 and p40, encoded by two separate genes, IL-12A and IL-12B, respectively. IL-12 is produced in response to immune stimuli by dendritic cells, macrophages, neutrophils, and by human B-lymphoblastoid cells, and has been known as an important stimulator of immune cell activity, in particular of T cells and natural killer cells, which are, among other effects, stimulated to secrete IFN-γ by IL-12. IFN-γ, in turn, is known to stimulate expression of immune checkpoint blockade proteins on non-immune cells, e.g. of PD-L1, a mechanism used by cancer cells to evade the immune system (Abiko et al. (2015), British journal of cancer 112(9): 1501; Quetglas et al. (2015) Cancer Research 75(15 Supplement): 281). Due to the known immunostimulatory effects of IL-12, it was attempted to use a recombinant measles virus expressing both subunits of IL-12 as a vaccine to improve immune response against measles virus. However, it was found that the transgene had a detrimental effect on the neutralizing antibody response and that lymphoproliferative responses were not improved (Hoffman et al. (2003), J Infect Dis 188:1553).
Oncolytic viruses (OV) which replicate selectively in tumor cells are an emerging modality of cancer treatment. Aside from direct cytopathic effects and lysis of tumor cells, interactions of OV with the immune system can trigger systemic anti-tumor immunity. OV have been modified to express immunomodulatory transgenes to further enhance these effects (Melcher et al., Mol Ther. 2011, 19: 1008-1016). The vaccinia virus JX-594 and herpesvirus talimogene laherpavec (TVEC), both harboring GM-CSF, have shown promising results in clinical phase II and III trials (Heo et al., Nat Med. 2013, 19: 329-336 and Andtbacka et al. J Clin Oncol. 2013, 31, suppl; abstr LBA9008).
RNA viruses, in particular members of the family Paramyxoviridae like, e.g. measles virus (MV), have also shown potential use in oncolysis. Viruses of the family Paramyxoviridae are negative-sense single-stranded RNA viruses and include human pathogens like, e.g. human parainfluenza viruses, mumps virus, human respiratory syncytial virus, and measles virus. From wild type measles virus, several non-pathogenic strains, including a vaccine strain, have been derived, which have been shown to remain oncolytic. The measles virus vaccine strain has been developed as a vector platform to target multiple tumor entities and several clinical trials are ongoing (Russell et al., Nat Biotechnol. 2012, 30: 658-670). Recently, the capacity of oncolytic MV encoding GM-CSF to support the induction of a specific anti-tumor immune response in terms of a tumor vaccination effect was demonstrated (Grossardt et al. Hum Gene Ther. 2013, 24: 644-654.).
There is, however, still a need in the art for improved cancer therapies, in particular for improved oncolytic virus therapies. It is therefore an objective of the present invention to provide an improved oncolytic virus, which fully or partially avoids the short-comings of known oncolytic viruses.